Estrogens are clinically important in both men and women. They affect growth, differentiation, and the development of reproductive tissues, and also play a role in a variety of diseases. For instance, estrogen maintains bone density, and in the cardiovascular system, estrogen exerts anti-atherosclerotic effects by lowering circulating cholesterol levels.
Controlling the levels and/or effects of estrogen is important in most forms of breast cancer. More than 1.2 million people will be diagnosed with breast cancer this year worldwide. In the United States alone, nearly 211,300 women and 1,300 men are newly diagnosed with breast cancer each year. It is the second leading cause of cancer deaths in women today and is the most common cancer among women, excluding cancers of the skin.
Estrogen receptors are specialized proteins that bind to estrogen. These proteins are found in significant quantities within certain estrogen-sensitive tissues. Cells within breast tissue contain estrogen receptors, for example, and the binding of estrogen to the estrogen receptors stimulates these cells to proliferate. Many breast cancer tumors also contain significant levels of estrogen receptors, and are therefore called “estrogen receptor positive” (“ER+”).
One conventional method used to discontinue or slow down the growth and proliferation of breast cancer cells is to reduce the effects of estrogen. The growth of ER+ breast cancer cells can generally be controlled by blocking the estrogen receptors, lowering hormone levels, and/or reducing the number of receptors available to receive growth signals. A conventional method to treat or help prevent the occurrence of breast cancer is by administering selective estrogen receptor modulators (“SERMs”), which block the estrogen receptors by preventing the growth signals from reaching the cells. SERMs target specific estrogen receptors in the body and either stimulate or depress an estrogen-like response, depending upon the particular organ. In breast cells, SERMs have antagonistic properties and block the effects of estrogen, thereby slowing the growth of breast cancer cells.
Tamoxifen (available under the trade name NOLVADEX from AstraZenica PLC; London, UK) is a commonly used SERM, which is used to treat advanced and early stage breast cancer. Tamoxifen is also used as therapy for the primary prevention of breast cancer. Although tamoxifen has been used to treat breast cancer for nearly twenty years, it has some serious drawbacks. Tamoxifen therapy may increase the risk of cancer of the uterine lining (i.e., endometrial cancer and sarcoma), blood clots within deep veins (i.e., deep vein thrombosis), blood clots in the lungs (i.e., pulmonary embolism), and cataracts. Other adverse side effects can include hot flashes, vaginal discharge, and menstrual irregularities.
Controlling the levels and/or effects of estrogen is also important in the treatment and prevention of osteoporosis. Osteoporosis is a common skeletal disorder characterized by a progressive decrease in bone mass and density; causing bones to become abnormally thin, weakened, and easily fractured. Although bone density naturally begins to decrease at approximately 35 years of age, women are disproportionately at risk for osteoporosis after menopause due to declining production of estrogen. After menopause, in women who are not receiving hormonal therapy, estradiol levels are generally about 10-20 pg/ml. The average level of estradiol needed to maintain healthy bones in menopausal women is about 40-50 pg/ml. Osteoporosis is the most significant health hazard associated with menopause; it affects 25% of women over the age of 65.
Osteoporosis is a significant public health threat for an estimated 44 million Americans. In the United States today, 10 million individuals are estimated to already have the disease, and almost 34 million more are estimated to have low bone mass, placing them at increased risk for osteoporosis. Of the 10 million Americans estimated to have osteoporosis, 8 million are women and only 2 million are men.
Because estrogen is associated with the proliferation of cells, the clinical aim in osteoporosis treatment is to increase the effect of estrogen (the opposite clinical goal of many breast cancer treatments). Conventional osteoporosis therapies include antiresorptive drugs, bone-building agents, and non-pharmacological intervention. Bisphosphonates are antiresporptive drugs that are widely used for the prevention and treatment of osteoporosis; they inhibit the breakdown and removal of bone (i.e., resorption) and are typically the first choice for osteoporosis treatment and prevention. However, in addition to adverse side effects, such as abdominal pain, nausea, and muscle and joint pain, some patients who take bisphosphonates also develop severe digestive reactions including irritation, inflammation or ulceration of the esophagus. These reactions can cause chest pain, heartburn or difficulty or pain upon swallowing. Raloxifene is another SERM commonly used to treat osteoporosis, but it carries the risk of blood clots and may cause a variety of side effects, including coughing blood, severe headaches, loss of speech, coordination or vision, pain or numbness in the arms, chest or legs, and shortness of breath. Still another conventional treatment for osteoporosis is estrogen-progestin therapy, but this approach is associated with side effects such as vaginal bleeding, bloating, nausea, headaches, and fluid retention. Estrogen-progestin therapy is no longer a first-line treatment for osteoporosis in postmenopausal women because of increases in the risk of breast cancer, stroke, blood clots, and perhaps coronary disease.
Conventional treatments for estrogen-related disease have substantial drawbacks; many are only partially effective and have adverse side effects, and few provide a cure for associated conditions. Present conventional methods to treat estrogen-related diseases may not be suitable for every patient. For the foregoing reasons and others, there is a need for a clinical intervention that can be used to control the regulation of estrogen signaling. Such an intervention would be an important tool to treat or prevent diseases and health conditions that are related to levels of estrogen; for example, breast cancer and osteoporosis. An understanding of the biomolecular pathway responsible for these conditions would be of significant importance in treating, and ultimately curing these conditions. A cell line that can be used as a clinical model in testing therapeutic interventions and diagnostic techniques would also be quite useful in this regard.